Start Warfarin, Have a Stroke?

Action Points

Patients initiating warfarin may be at an increased risk of stroke during the first 30 days of treatment.

Decreased stroke risks were observed as expected later than 30 days after initiation of warfarin.

Starting warfarin for preventing stroke in patients with atrial fibrillation appeared to be associated with a transiently increased risk of ischemic stroke before the preventive effects kicked in, a large case-control study showed.

Compared with not taking any antithrombotics, initiating warfarin was associated with a greater risk of ischemic stroke in the first 30 days (2.1% versus 1.3%; rate ratio 1.71, 95% CI 1.39-2.12), with a peak at 3 days, according to Samy Suissa, PhD, of McGill University in Montreal, and colleagues.

"There has long been a well-founded theoretical concern that early initiation of warfarin may be related to a hypercoagulable phase. The conventional wisdom is that this effect may be only in the first few days of warfarin treatment in the therapeutic INR range," according to John Erwin III, MD, of Scott and White Heart and Vascular Institute, who was not involved in the study. "This study seems to confirm the theoretical concern and raise the question as to whether this effect may actually persist longer than the conventional teaching."

"This adds fuel to the fire that the newer novel oral anticoagulant therapies are superior based upon their mechanisms and based upon the speed at which they achieve therapeutic anticoagulation levels in patients with nonvalvular atrial fibrillation," he said in an interview.

"It is important to note, however, that the short bridging time (2 days) between the study drugs and warfarin may not have been adequate to provide optimal anticoagulation, and thus it is possible that longer bridging times would have abrogated the transient increased risk observed with warfarin," Suissa and colleagues wrote.

To explore the possible connection between warfarin initiation and risk of ischemic stroke, they looked at data from adult patients who were newly diagnosed with atrial fibrillation from 1993 through 2008 and included in the U.K. Clinical Practice Research Datalink, a primary care database. The current analysis included 5,519 patients who had an ischemic stroke during the study period and 55,022 control patients matched by age, sex, date of atrial fibrillation diagnosis, and time since diagnosis.

The elevated risk of ischemic stroke seen within 30 days of initiating warfarin occurred in patients both with and without a prior history of stroke, although the relationship was stronger among the patients who had such a history (RR 2.45 versus 1.30).

The short-term increase in stroke risk has biological plausibility, according to the researchers.

"While warfarin blocks the activation of clotting factors II, VII, IX, and X, it also deactivates protein C and protein S, two endogenous anticoagulants. Protein C has a short half-life (8 hours), and thus rapid depletion of this protein can theoretically lead to a transient hypercoagulable state," they wrote. "Supporting this hypothesis is the increased risk observed in the first 7 days of use, which [is] also concordant with the time of onset of warfarin-induced skin necrosis, another known but rare manifestation of this hypercoagulable state."

Sanjeev Saksena, MD, of Rutgers-Robert Wood Johnson Medical School, said the current study likely would not have an effect on practice in the short term.

The study "is a hypothesis-generating report and will need carefully done large clinical trials to examine the proposed risk of a hypercoagulable state with short duration of warfarin exposure," he told MedPage Today. "There are many limitations to such population studies, which have limited clinical data on the clinical scenario [and] execution and monitoring of therapy that require more thorough clinical study in a more detailed data collection approach that controls for multiple variables and variable risks in this population."

It is possible, however, that there could be implications for practice in the future, he said. Closer surveillance might be required when patients are being transitioned from a newer agent to warfarin and when patients are starting on warfarin after a new diagnosis of atrial fibrillation following a stroke, he said, adding that there also could be a greater role for bridging anticoagulant therapy.

Suissa and colleagues acknowledged some limitations of their analysis, including the use of written prescriptions to determine drug use, the possibility of underreported or misclassified strokes, and the lack of consistently recorded INR information.

The study was funded by Bristol-Myers Squibb and Pfizer. Two of the study authors are recipients of a Chercheur-Boursier Award from the Fonds de la recherche en santé du Québec (FRSQ) and Suissa is the recipient of the James McGill Chair.

Suissa has received research funding and has participated in advisory committees for Bristol-Myers Squibb, Boehringer Ingelheim, and Bayer-Schering. One of the authors is an employee of Bristol-Myers Squibb.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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